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203


An integrated expression phenotype mapping approach defines common variants in LEP, ALOX15 and CAPNS1 associated with induction of IL-6

Fairfax, Benjamin P; Vannberg, Fredrik O; Radhakrishnan, Jayachandran; Hakonarson, Hakon; Keating, Brendan J; Hill, Adrian V S; Knight, Julian C
Interleukin-6 (IL-6) is an important modulator of inflammation and immunity whose dysregulation is associated with a number of disease states. There is evidence of significant heritability in inter-individual variation in IL6 gene expression but the genetic variants responsible for this remain to be defined. We adopted a combined approach of mapping protein and expression quantitative trait loci in peripheral blood mononuclear cells using high-density single-nucleotide polymorphism (SNP) typing for approximately 2000 loci implicated in cardiovascular, metabolic and inflammatory syndromes to show that common SNP markers and haplotypes of LEP (encoding leptin) associate with a 1.7- to 2-fold higher level of lipopolysaccharide (LPS)-induced IL-6 expression. We subsequently demonstrate that basal leptin expression significantly correlates with LPS-induced IL-6 expression and that the same variants at LEP which associate with IL-6 expression are also major determinants of leptin expression in these cells. We find that variation involving two other genomic regions, CAPNS1 (encoding calpain small subunit 1) and ALOX15 (encoding arachidonate 15-lipoxygenase), show significant association with IL-6 expression. Although this may be a subset of all such trans-acting effects, we find that the same ALOX15 variants are associated with induced expression of tumour necrosis factor and IL-1beta consistent with a broader role in acute inflammation for ALOX15. This study provides evidence of novel genetic determinants of IL-6 production with implications for understanding susceptibility to inflammatory disease processes and insight into cross talk between metabolic and inflammatory pathways. It also provides proof of concept for use of an integrated expression phenotype mapping approach.
PMCID:2807371
PMID: 19942621
ISSN: 1460-2083
CID: 5477732

Comprehensive Candidate Gene Association Study of Peripheral Arterial Disease in Type 2 Diabetes [Meeting Abstract]

Eraso, Luis H.; Ferguson, Jane; Mehta, Nehal N.; Li, Mingyao; Keating, Brendan; Mohler, Emile R., III; Reilly, Muredach P.
ISI:000283234800470
ISSN: 1079-5642
CID: 5479052

Gene-Centric Approach Identifies New and Known Loci for Factor VIII Activity and Von Willebrand Factor Antigen In the Candidate Gene Association Resource (CARe) Consortium [Meeting Abstract]

Tang, Weihong; Cushman, Mary; Basu, Saonli; Green, David; Reiner, Alexander P.; Delaney, Joseph A.; Lange, Leslie A.; Smith, Nicholas L.; Tracy, Russell P.; Wilson, James G.; Tofler, Geoffrey; Yang, Qiong; Keating, Brendan J.; Taylor, Herman; Jacobs, David; O\Donnell, Christopher J.; Folsom, Aaron R.
ISI:000289662200807
ISSN: 0006-4971
CID: 5479062

Concept, design and implementation of a cardiovascular gene-centric 50 k SNP array for large-scale genomic association studies

Keating, Brendan J; Tischfield, Sam; Murray, Sarah S; Bhangale, Tushar; Price, Thomas S; Glessner, Joseph T; Galver, Luana; Barrett, Jeffrey C; Grant, Struan F A; Farlow, Deborah N; Chandrupatla, Hareesh R; Hansen, Mark; Ajmal, Saad; Papanicolaou, George J; Guo, Yiran; Li, Mingyao; Derohannessian, Stephanie; de Bakker, Paul I W; Bailey, Swneke D; Montpetit, Alexandre; Edmondson, Andrew C; Taylor, Kent; Gai, Xiaowu; Wang, Susanna S; Fornage, Myriam; Shaikh, Tamim; Groop, Leif; Boehnke, Michael; Hall, Alistair S; Hattersley, Andrew T; Frackelton, Edward; Patterson, Nick; Chiang, Charleston W K; Kim, Cecelia E; Fabsitz, Richard R; Ouwehand, Willem; Price, Alkes L; Munroe, Patricia; Caulfield, Mark; Drake, Thomas; Boerwinkle, Eric; Reich, David; Whitehead, A Stephen; Cappola, Thomas P; Samani, Nilesh J; Lusis, A Jake; Schadt, Eric; Wilson, James G; Koenig, Wolfgang; McCarthy, Mark I; Kathiresan, Sekar; Gabriel, Stacey B; Hakonarson, Hakon; Anand, Sonia S; Reilly, Muredach; Engert, James C; Nickerson, Deborah A; Rader, Daniel J; Hirschhorn, Joel N; Fitzgerald, Garret A
A wealth of genetic associations for cardiovascular and metabolic phenotypes in humans has been accumulating over the last decade, in particular a large number of loci derived from recent genome wide association studies (GWAS). True complex disease-associated loci often exert modest effects, so their delineation currently requires integration of diverse phenotypic data from large studies to ensure robust meta-analyses. We have designed a gene-centric 50 K single nucleotide polymorphism (SNP) array to assess potentially relevant loci across a range of cardiovascular, metabolic and inflammatory syndromes. The array utilizes a "cosmopolitan" tagging approach to capture the genetic diversity across approximately 2,000 loci in populations represented in the HapMap and SeattleSNPs projects. The array content is informed by GWAS of vascular and inflammatory disease, expression quantitative trait loci implicated in atherosclerosis, pathway based approaches and comprehensive literature searching. The custom flexibility of the array platform facilitated interrogation of loci at differing stringencies, according to a gene prioritization strategy that allows saturation of high priority loci with a greater density of markers than the existing GWAS tools, particularly in African HapMap samples. We also demonstrate that the IBC array can be used to complement GWAS, increasing coverage in high priority CVD-related loci across all major HapMap populations. DNA from over 200,000 extensively phenotyped individuals will be genotyped with this array with a significant portion of the generated data being released into the academic domain facilitating in silico replication attempts, analyses of rare variants and cross-cohort meta-analyses in diverse populations. These datasets will also facilitate more robust secondary analyses, such as explorations with alternative genetic models, epistasis and gene-environment interactions.
PMCID:2571995
PMID: 18974833
ISSN: 1932-6203
CID: 5477722

Large-Scale Candidate Gene Association with Human Heart Failure in 2 Referral Populations [Meeting Abstract]

Cappola, Thomas P.; Li, Mingyao; He, Jing; Ky, Bonnie; Gilmore, Joan; Keating, Brendan; Reilly, Muredach P.; Syed, Faisel; Dorn, Gerald W.
ISI:000258845200046
ISSN: 0009-7330
CID: 5479022

Large-Scale Candidate Gene Association with Human Heart Failure [Meeting Abstract]

Cappola, Thomas; Li, Mingyao; He, Jing; Ky, Bonnie; Gilmore, Joan; Keating, Brendan; Reilly, Muredach; Syed, Faisel; Matkovich, Scot; Dorn, Gerald
ISI:000262104503535
ISSN: 0009-7322
CID: 5479032

High Density SNP Association Analysis of Potential HDL Candidate Genes Reveals Molecular Architecture and Functionally Relevant Domains: Focus on CETP [Meeting Abstract]

Stylianou, Loannis M.; Edmondson, Andrew; Li, Mingyao; DerOhannessian, Stephanie L.; Khora, Amit; Wolte, Megan L.; Keating, Brendan J.; Reilly, Muredach P.; Rader, Daniel J.
ISI:000262104504547
ISSN: 0009-7322
CID: 5479042

Identification of common genetic variation that modulates alternative splicing

Hull, Jeremy; Campino, Susana; Rowlands, Kate; Chan, Man-Suen; Copley, Richard R; Taylor, Martin S; Rockett, Kirk; Elvidge, Gareth; Keating, Brendan; Knight, Julian; Kwiatkowski, Dominic
Alternative splicing of genes is an efficient means of generating variation in protein function. Several disease states have been associated with rare genetic variants that affect splicing patterns. Conversely, splicing efficiency of some genes is known to vary between individuals without apparent ill effects. What is not clear is whether commonly observed phenotypic variation in splicing patterns, and hence potential variation in protein function, is to a significant extent determined by naturally occurring DNA sequence variation and in particular by single nucleotide polymorphisms (SNPs). In this study, we surveyed the splicing patterns of 250 exons in 22 individuals who had been previously genotyped by the International HapMap Project. We identified 70 simple cassette exon alternative splicing events in our experimental system; for six of these, we detected consistent differences in splicing pattern between individuals, with a highly significant association between splice phenotype and neighbouring SNPs. Remarkably, for five out of six of these events, the strongest correlation was found with the SNP closest to the intron-exon boundary, although the distance between these SNPs and the intron-exon boundary ranged from 2 bp to greater than 1,000 bp. Two of these SNPs were further investigated using a minigene splicing system, and in each case the SNPs were found to exert cis-acting effects on exon splicing efficiency in vitro. The functional consequences of these SNPs could not be predicted using bioinformatic algorithms. Our findings suggest that phenotypic variation in splicing patterns is determined by the presence of SNPs within flanking introns or exons. Effects on splicing may represent an important mechanism by which SNPs influence gene function.
PMCID:1904363
PMID: 17571926
ISSN: 1553-7404
CID: 5477712

A hallmark of balancing selection is present at the promoter region of interleukin 10

Wilson, J N; Rockett, K; Keating, B; Jallow, M; Pinder, M; Sisay-Joof, F; Newport, M; Kwiatkowski, D
As an anti-inflammatory mediator IL10 is beneficial in certain contexts and deleterious in others. As increased production of IL10 favours protection against inflammatory disease, whereas low production promotes elimination of foreign pathogens by the host, we investigated the possible influence of balancing selection at this locus. We began by resequencing 48 European and 48 African chromosomes across 2.2 kb of the IL10 promoter region, and compared this with four neighbouring gene regions: MK2, IL19, IL20 and IL24. Analysis of nucleotide diversity showed a positive Tajima's D-test for IL10 in Europeans, of borderline statistical significance (1.89, P=0.05). Analysis of F(st) values showed significant population divergence at MK2, IL19, IL20 and IL24 (P<0.01) but not at IL10. Taken together, these findings are consistent with the hypothesis that balancing selection has played a role in the evolution of polymorphisms in the IL10 promoter region.
PMID: 16943796
ISSN: 1466-4879
CID: 5479362

Implications of inter-population linkage disequilibrium patterns on the approach to a disease association study in the human MHC class III

Hanchard, Neil; Diakite, Mahamadou; Koch, Oliver; Keating, Brendan; Pinder, Margaret; Jallow, Muminatou; Sisay-Joof, Fatou; Nijnik, Anastasia; Wilson, Jonathan; Udalova, Irina; Kwiatkowski, Dominic; Rockett, Kirk
There is presently much interest in utilizing patterns of linkage disequilibrium (LD) to further genetic association studies. This is particularly pertinent in the class III region of the human major histocompatibility complex (MHC), which has been extensively studied as a disease susceptibility locus in a number of ethnic groups. To date, however, few studies of LD in the MHC have considered non-Caucasian populations. With the advent of large-scale haplotyping of the human genome, the question of utilizing LD patterns across populations has come to the fore. We have previously used LD mapping to direct an MHC class III association study in a UK Caucasian population. As an extension of this, we sought to determine to what extent the pattern of LD observed in that study could be used to conduct a similar study in a West African Gambian population. We found that broad patterns of LD were similar in the two populations, resulting in similar candidate region delineations, but at a higher resolution, marker-specific patterns of LD and population-dependent allele frequencies confounded the choice of regional tagging SNPs. Our results have implications for the applicability of large-scale haplotype maps such as the HapMap to complex regions like the MHC.
PMID: 16738941
ISSN: 0093-7711
CID: 5477702